2540 - A Combined Phase 0/1b Trial of ATM Inhibitor AZD1390 in Combination with Radiation in Patients with Newly-Diagnosed, MGMT-Unmethylated Glioblastoma

W. R. Kennedy, N. Sanai, S. Desai, T. Margaryan, J. Molloy, C. Lo Cascio, M. Elliott, J. Harmon, A. Hong, E. Luna Melendez, J. Wanebo, K. Braun, Y. Umemura, R. D. Kraus, I. J. Barani Jr, W. Yoo, A. Tovmasyan, A. C. Tien, and S. Mehta; Ivy Brain Tumor Center, Barrow Neurological Institute, Phoenix, AZ

Purpose/Objective(s): Ataxia-telangiectasia mutated (ATM) gene mediates acute phase DNA damage repair pathways. Inhibition of ATM is theorized to amplify the effects of radiotherapy (RT). AZD1390 is a first-in-class, investigational ATM inhibitor. We conducted a combined phase 0/1b study to evaluate AZD1390 pharmacokinetics (PK) and pharmacodynamics (PD) in patients with newly-diagnosed glioblastoma (GBM), graduating patients to a phase 1b study evaluating a therapeutic regimen of AZD1390 with concurrent RT in O6-methylguanine methyltransferase (MGMT) unmethylated tumors exceeding a prespecified PK threshold in non-enhancing tumor. Materials/

Methods: Patients with presumed newly-diagnosed GBM were enrolled in a phase 0 study receiving 3 days of AZD1390 prior to planned resection 4-6 or 23-25 hours following the final dose. Tumor tissue, cerebrospinal fluid (CSF), and plasma were collected. Total and unbound drug concentrations were measured using validated LC-MS/MS methods. ATM inhibition was assessed by quantification of pRAD50 after 5 Gy ex vivo irradiation in surgical tissue compared to non-irradiated control tissue. A PK ‘trigger’, 2nM unbound drug levels in Gd-non-enhancing tumor, determined eligibility for the therapeutic phase 1b expansion portion of the study. Patients with MGMT-unmethylated tumors exceeding this PK threshold were eligible for expansion phase dosing of AZD1390 with concurrent RT, 60 Gy in 30 fractions using volumetric-modulated arc therapy (VMAT). Patients with MGMT methylated tumors were not eligible for the expansion phase and proceeded with temozolomide (TMZ) plus RT followed by maintenance TMZ.
Results: Seventeen patients were enrolled onto the phase 0 portion of the study. Three patients were excluded from the PK analysis due to dosing deviation (n=1) or non-GBM diagnosis (n=2). For the 14 patients included in the PK analysis, the mean unbound concentration of AZD1390 in Gd-non-enhancing tumor was 12.4 and 4.4 pmol/g, for the 4-6 hours preop (n=10), and 23-25 hours preop (n=4) time cohorts, respectively. The suppression of pRAD50 levels after ex vivo RT was observed in AZD1390- treated patients (median 0.2% for 4-6-hours cohorts and 1.9% for 23-25 hours cohort vs 32.3% for control cohort). One non-serious adverse event of grade 3 hyperammonemia was reported and deemed potentially related to AZD1390. No serious adverse events related to AZD1390 were reported. As of November 2023, 3 patients with MGMT-unmethylated tumors have completed therapeutic dosing of AZD1390 with concurrent radiotherapy with a median clinical follow-up of 2.3 months.
Conclusion: AZD1390 achieved pharmacologically-relevant concentrations in non-enhancing, newly- diagnosed GBM tissue and effectively inhibits ATM as measured by suppression of radiation-induced pRAD50 increases. AZD1390 with concurrent RT is well-tolerated with initial follow-up. Updated follow-up will better determine long-term safety and efficacy of this first-in-class combination.